1. Field of the Invention:
This invention relates to a pharmaceutical preparation in pressure-sensitive adhesive tape form that permits the percutaneous absorption of nitroglycerin over a long period of time at a controlled rate.
2. Description of the Prior Art:
Nitroglycerin is used as a medicine for the treatment and for the prevention of heart disease such as angina pectoris, myocardial infarction, cardiac insufficiency, and the like. When nitroglycerin is administered by, for example, intravenous injection, its effects are lost after a very short period of time. Also, because the nitroglycerin in the blood is thereby raised to a high level for a short period of time, there are the disadvantages of side effects such as headache, dizziness, orthostatic hypotension, etc. In order to keep the blood level of nitroglycerin at a fixed value for relatively long periods of time, a preparation that has a layer of adhesive that contains nitroglycerin on a backing can be used, and the nitroglycerin can be absorbed percutaneously. The drug nitroglycerin is relatively easily absorbed through the skin. For that reason, if adhesives such as natural rubber, silicone resin, etc., in which nitroglycerin is relatively insoluble are used, the skin adhesive partition coefficient of nitroglycerin is high, and the permeation rate through the skin is therefore too high, resulting in the side effects mentioned above. In order to achieve the effective use of the pharmacological effects of nitroglycerin, continuous percutaneous absorption by which the blood level of nitroglycerin of 0.05-2.0 ng/ml is maintained is preferable. For this purpose, a number of steps have been taken, such as the selection of a base by which the rate of percutaneous absorption of the nitroglycerin can be controlled.
Preparations that contain nitroglycerin have been disclosed in, for example, Japanese Laid-Open Patent Publication Nos. 56-133381, 57-77617, and 55-2604. All of these preparations make use of bases that can control the release of nitroglycerin more readily than with bases such as those mentioned above, including natural rubber, polyisobutylene, etc. For example, the preparation disclosed in Japanese Laid-Open Patent Publication No. 57-77617 has a copolymer as the adhesive base that can be obtained by the copolymerization of dodecyl methacrylate, a functional monomer such as acrylic acid, and a specific alkyl (meth)acrylate. However, when this kind of preparation is made by the ordinary method for the application using solvents, the solvent and the nitroglycerin volatilizes together when the solvent is removed or at the time of drying, because the compatibility of the nitroglycerin and the adhesive base material is low. Nitroglycerin is explosive, so a large amount of volatilized nitroglycerin is extremely dangerous during manufacture. There has been an impregnation method by which the above-mentioned preparation can be produced without any danger. In this method, first, an adhesive layer that does not contain any drug is formed on top of the backing, and a soft ointment or the like that contains nitroglycerin is applied to this adhesive layer and left to mature so that nitroglycerin is transferred to the adhesive layer. However, it is difficult by use of this impregnation method to achieve an adhesive base in which the nitroglycerin is distributed uniformly at a high concentration. In this way, the preparation that can be obtained by the impregnation method has a small amount of nitroglycerin in the adhesive base, so pharmacological effectiveness over long periods of time is not achieved. Moreover, per unit of surface area, the amount of nitroglycerin is small, so it is necessary to use a large surface area of the preparation in order to achieve the percutaneous absorption of a fixed amount of nitroglycerin.
Preparations that attain transdermal-controlled administration of nitroglycerin without selection of the variety of the adhesive base material have been proposed by, for example, Japanese Patent Publication No. 54-16566, in which a layer of base material that contains a high concentration of nitroglycerin is formed on a backing, and on this layer, a membrane (i.e. a controlled release membrane) that has micropores and then an adhesive layer are placed in that order to form the preparation. Japanese Laid-Open Patent Publication Nos. 55-94316, 57-14522, 57-500831, and 57-59806 disclose a preparation that is composed of two separate parts, a base layer of non-adhesive resin such as polyvinyl alcohol containing nitroglycerin therein and an adhesive layer by which this base material that contains nitroglycerin is made to adhere to the skin surface. Japanese Laid-Open Patent Publication Nos. 59-207149 and 56-125311 disclose preparations in which a plurality of base layers that contain different concentrations of nitroglycerin are disposed on a backing, and an adhesive layer is disposed thereon. A preparation has been proposed in which the adhesive layer contains nitroglycerin that has been microencapsulated in a micro-pore film. However, the manufacture of all of these preparations is complicated, which makes difficulties in obtaining a preparation that contains nitroglycerin at low cost.